Mono-glycol esters of 3, 5-di-iodo-4-pyridone-nu-acetic acid X-ray contrast agentsin bronchography



3,2135% Patented Feb. 13, 1962 This invention relates, generally, tonovel organic chemical compounds useful as radiopaque media for X-raydiagnostics and, more particularly, it relates to certain hydroxy estersof 3,5-diiodo-4-pyridone-N-acetic acid which have been found to beadmirably suited for use as X-ray contrast media for bronchography.

Heretofore, various contrast media requiring different methods ofadministration have been proposed for use in bronchography, and numerouspapers have been published in the medical and allied journals concerningthe techniques of this form of diagnostic treatment including, forexample, premedicatiou, anesthesia, application of radiopaque agents,and contrast media. It appears quite clearly from these experiences thatpresent contrast media for bronchographical applications are notentirely satisfactory.

Thus, since the lungs contribute to the distribution of the contrastmedium through their inspiratory suction, there exists the ever presentdanger that the medium might penetrate too far into the lung periphery.In evaluating the usefulness of any contrast medium intended for use inbronchography, it is therefore essential to know how residual quantitiesof the medium which are not removed via the air passages are handled bythis organ. For ex ample, certain known iodized oils have the distinctad vantage of being non-irritating, but residues of these oils arepoorly eliminated from the lungs, with the result that the lung tissuecan be damaged through use of such media.

Certain known forms of water-soluble contrast media are combined with ahigh-viscosity carrier substance, such that the high-viscosity of theresulting preparation will mitigate seepage of the media into theperiphery of the lungs. Being hypertonic solutions, however, these formsof contrast media severely irritate the bronchial mucosa, necessitatingextensive use of anesthetics. Moreover, residues of the viscositycarrier have been detected in the nonrespiratory portions of the lung,where they may initiate untoward tissue reactions.

In addition to the foregoing types of media, certain iodine-containingesters in the form of aqueous contrast medium suspensions have also beenemployed heretofore for bronchography. While such suspensions usually donot irritate the bronchial mucosa, they do produce the undesirable sideeffects of elevated temperatures, which often last for 3 to 4 days, aswell as settling of the medium in the lung periphery.

The present invention is based, in part, on our discovery that certainesters of iodized contrast media that contain one or more hydroxylgroups in the ester substituent, form ideal contrast media forbronchography.

In general, the compounds of the invention are produced by reacting,according to conventional procedures, iodized contrast media containingfree carboxyl groups with a large excess of dihydric or polyhydricalcohols, in such manner that only one hydroxyl group of thepolyhyd'roxyl reagent reacts with the carboxyl group in ester formation.

As the carboxyl-bearing reagents used in the production of the novelcontrast media of our invention, we prefer to employ substances whichhave shown good conmedia should have particle sizes falling trastproperties in X-ray diagnostics, in general, such as3,S-diiodo-4-pyridone-N-acetic acid. Virtually any polyhydric alcoholcan be employed as the hydroxylbearing reagent including, by way ofillustration, a-glycols, fi-glycols, glycerol, etc.

The novel contrast media of our invention may be represented in generalby the following structural formula:

(I) c n2o00n N l! 5 3 I 4 I wherein R is an alkyl group carrying atleast one hydroxyl substituent.

We prefer to employ the new esters for bronchography in the form ofaqueous suspensions. These suspensions are prepared by the addition of asuitable agent for increasing the viscosity of the preparation, and asuitable agent for increasing the viscosity of the preparation, and asuitable dispersing agent. Typical viscosity-increasing carriers includecarboxylated cellulose, cellulose ether, polyvinyl alcohol, etc. Asdispersing agents, we prefer to employ a non-ionic emulsifier, such asreaction products of fatty acids, fatty alcohols, or neutral fats withethylene oxide, or emulsifiers of the so-called Tween series(polyoxyalkylene derivatives of hexitol anhydride partial long chainfatty acid esters). Preferably, the new predominantly within the rangeof 5-30 microns.

In the clinical testing of the contrast media of the invention inbronchography, the following results have been obtained:

(1) No irritation of the bronchial mucosa was produced, so that thebronchographical observations were not disturbed by coughing;

(2) The media showed surprisingly strong adhesion in the bronchialsystem, which prevented migration of the agent into the lung periphery;

(3) The new compounds were found to, be rapidly and completely absorbedby the organism, with no contrast medium being visible in the lungs oncontrol X-rays taken 36 hours later;

(4) No temperature rise after the bronchography.

It is believed that the invention may be best understood by reference tothe following specific examples which illustrate the preparation oftypical contrast media as defined above:

EXAMPLE I Monoglycol ester of 3,5-diiodo-4-pyrid0ne-N-acetic acid,asrepresented by the formula:

(311200 0 CHgCHzOH was observed in the patients I t n I I I Y o Ethyleneglycol, in amount 200 grams, 150 cubic centimeters of benzene, and 4cubic centimeters of concentrated sulfuric acid were mixed in anagitated flask with a superimposed water separator carried thereon.After addition of grams of 3,5-diiodo-4-pyridone-N-acetic acid, thereaction mixture was heated at the boil for 5 hours. Initially, thesubstance dissolved, and in the course of the reaction the desired esterprecipitated in part. Cooling overnight completed the precipitation.Following suction-filtration the residue was washed first with acetoneand then with highly dilute soda solution and water. The resultantmonoglycol ester of 3,5-diiodo- 4-pyriclone-N-acetic acid recrystallizesreadily from acetone. It crystallizes in the form of White crystalsmelting at 1S6-189 C. (Yield: 100 grams.)

EXAMPLE II 'M0no-1,2-pr0pylene glycol ester of 3,5-diiod-4-pyrid0ne-N-acetic acid, as represented by the formula:

(III) omooocmoncncn,

1,2-propy1ene glycol, in amount 105 grams, 115 cubic centimeters ofbenzene, and 4 cubic centimeters of concentrated sulfuric acid weremixed in the same apparatus as described in Example 1. Following theaddition of 100 grams of 3,5-diiodo-4-pyridone-N-acetic acid, thereaction mixture was heated at the boil for 5 hours, and the waterformed during the reaction was collected in the water separator.Thereafter, the benzene was distilled off under vacuum, and the residuewas poured into 400 cubic centimeters of water. This caused the desiredmono-1,2- propylene glycol 3,5-diiodo-4pyridone-N-acetate toprecipitate. The White crystals were filtered ofi by suction and washedsuccessively with a highly dilute soda solution and with water. Thecompound can be recrystallized from ethanol or acetone. It melts at169-172 C. (Yield: 90 grams.)

EXAMPLE III Mon0(2,2-dimethyl-1,3-prop'anediol) ester of 3,5-dii0do-4-pyridone-N-acetic acid, as represented by the formula:

CHuC O O CHzCHaOH l l (111: l. ll

EXAMPLE IV 3,5-diiodo4-pyridone-N-acelylglycerol, as represented by theformula:

(V) C|JH2C0OCH2OHCEOHCH2 N l l I of 3,S-diiodo-4-pyridone-N-acetic boilas described in Example II,

Twenty (20) grams acid were heated to the with 46 grams of glycerol, 50cubic centimeters of henzene, and 2.5 cubic centimeters of concentratedsulfuric acid for 3 /2 hours. The precipitated3,5-diiodo-4-pyridone-N-acetylglycerol can be purified byrecrystallization from water, The compound forms colorless crystals ofmelting point -124 C.

Having thus described the subject matter of our invention, what it isdesired to secure by Letters Patent is:

1. A chemical compound represented by the formula:

OHzCOO-R N l l wherein R is a member selected from the group consistingof monoglycol and mono-1,2-propylene glycol.

2. The monoglycol ester of 3,5-diiodo-4-pyridone-N- acetic acid.

3. The mono-1,2-propylene glycol ester of 3,5-diiodo-4-pyn'done-N-acetic acid.

4. A composition of matter for use as a contrast medium in bronchographythat comprises, an aqueous suspension of a compound represented by theformula:

CHaC O OR wherein R is a member selected from the group consisting ofmonoglycol and mono-1,2-propylene glycol.

7. Process for rendering the bronchi of a subject radiopaque thatcomprises introducing into said bronchi the mono-1,2-propylene glycolester of 3,5-diiodo-4-pyridone- N-acetic acid.

References Cited in the file of this patent UNITED STATES PATENTS2,064,944 Reitmann Dec. 22, 1936 2,272,484 Shelton Feb. 10, 1942 r2,505,634 Archer Apr. 2, 1950 2,870,063 LaMater Jan. 20, 1959 FOREIGNPATENTS 517,382 Great Britain Jan. '29, 1940

1. A CHEMICAL COMPOUND REPRESENTED BY THE FORMULA:
 6. PROCESS FORRENDERING THE BRONCHI OF A SUBJECT RADIOPAQUE THAT COMPRISES INTRODUCINGINTO SAID BRONCHI A COMPOUND OF THE FORMULA: